1. Field of the Invention
The invention provides new methods for synthesis of 2-aralkyloxyadenosines and 2-alkoxyadenosines. The invention is particularly useful for the synthesis of 2-[2-(4-chlorophenyl)ethoxy]adenosine.
2. Background
Adenosine is an endogenous substance with many biological functions. Many of these biological functions are a result of its role as the natural ligand for the P1 purinergic receptors, also known as adenosine receptors. There are four known subtypes of the adenosine receptor that have been identified and cloned from several mammalian species: A1, A2A, A2B, and A3. These receptors are prototypical G-protein coupled receptors and elicit their biological activities through typical signal transduction pathways.
Chemical modifications of adenosine have provided molecules which function as either agonists or antagonists and which bind selectively to the individual subclasses of adenosine receptors. The availability of such selective ligands has allowed the many biological functions of adenosine to be attributed to the individual receptor subclasses. In particular, it has been demonstrated that selective adenosine A2A receptor agonists, when applied topically, can significantly accelerate wound healing in animals with both normal and impaired healing capacity. For instance, CGS-21680, a 2-(aralkylamino)adenosine-5′-uronamide, significantly accelerated wound closure in healthy, normal mice (See Montesinos et. al. J. Exp. Med., 1997, 186: 1615-1620). Further, this same compound enhanced healing of excisional wounds in both normal and diabetic rats, compared to untreated rats, an effect that was blocked by the co-administration of a selective adenosine A2A receptor antagonist.
Additional adenosine compounds of interest are the selective adenosine A2A agonists known as 2-alkoxy- and 2-aralkoxy-adenosines. In particular, it has recently been shown that 2-[2-(4-chlorophenyl)ethoxy]adenosine promotes more rapid closure of excisional wounds in normal healthy mice than 0.01% becaplermin gel, an agent currently approved for use in the treatment of diabetic foot ulcers.
The preparation of 2-[2-(4-chlorophenyl)ethoxy]-adenosine and other 2-aralkyloxyadenosines and 2-alkoxyadenosines has involved the displacement of the chloro group of 2′,3′-O-(ethoxymethylidene)-2-chloroadenosine or 2′,3′-O-(isopropylidene)-2-chloroadenosine with the appropriate sodium or lithium (ar)alkoxide (See Marumoto et al. (1975), Chem. Pharm. Bull. 23: 759-774; Ueeda et al. (1991a), J. Med. Chem. 34: 1334-1339; Ueeda et al. (1991b), J. Med. Chem. 34: 1340-1344), followed by deprotection and purification of the desired product. Blocking of the 2′- and 3′-hydroxyl groups has been described as essential to prevent the formation of a 2→2′ polymeric product (Marumoto et al. (1975), Chem. Pharm. Bull. 23: 759-774; Ueeda et al. (1991a), J. Med. Chem. 34: 1334-1339). It has also been indicated that the liability of the glycosidic N-9→C-1′ bond to the acidic conditions required to remove the 2′,3′-blocking group contributes to the low yields observed in the preparation of these selective adenosine A2A agonists (Ueeda et al. (1991a), J. Med. Chem. 34: 1334-1339).
These synthetic routes are lengthy and often produce compounds in notably low yields. It thus would be desirable to have new methods to synthesize 2-aralkyloxyadenosines and 2-alkoxyadenosines. It would be particularly desirable to have new methods to synthesize 2-[2-(4-chlorophenyl)ethoxy]adenosine.